
Sulfobutyl ether-β-cyclodextrin, referred to hereafter as SBE-β-CD, is a sulfobutyl derivative of anionic cyclodextrin having high water solubility, and which is used as a novel pharmaceutical preparation auxiliary material. The SBE-β-CD can form noncovalent inclusion complexes with pharmaceutical molecules which improves the stability, water solubility, safety, and the biological activity of the therapeutic agents. The SBE-β-CD has little nephrotoxicity, can alleviate hemolysis, and modulate the rate of release of a medicine. At present, the SBE-β-CD has become commercialized and applied in injections, oral medicines, nasal preparations, ophthalmic drugs, and so on, and has special affinity toward forming inclusion complexes with nitrogen-containing medicines.
Since the SBE-β-CD is synthesized in a single method, a key of synthesis of the SBE-β-CD is to improve the yield thereof and find a method applicable to mass production.
Existing methods for synthesizing the SBE-β-CD involve subjecting hydroxyl groups on carbons of sites 2, 3, 6 of a β-cyclodextrin glucose unit to a substitution reaction using sulfobutyrolactone in an alkaline aqueous solution or by subjecting a β-cyclodextrin to hydroxyl group deprotonation with sodium in an organic solvent followed by sulfobutyrolactone substitution reaction.
As disclosed in U.S. Pat. No. 5,134,127, the SBE-β-CD is firstly synthesized by subjecting β-cyclodextrin and the 1,4-sulfobutyrolactone to a reaction in a sodium hydroxide aqueous solution, deionization, ultrafiltration, and freeze-drying are performed to obtain a pure product of the SBE-β-CD having a substitution degree of 7.0 to 7.1. Later, U.S. Pat. No. 6,153,746 makes improvements with reference to this method to obtain a series of the SBE-β-CD having different degrees of substitution through synthesis and separation. the SBE-β-CD is subjected to amplified synthesis, dialysis, ultrafiltration, active carbon decolourization, and precise filtering. The product aqueous solution is freeze dried to obtain SBE-β-CD having a substitution degree of 6.5. U.S. Pat. No. 7,635,773 uses the same reagents to carry out industrial production of the SBE-β-CD, after dialysis, active carbon decolourization, and precise filtering are performed, a product aqueous solution is subjected to spray drying to obtain the SBE-β-CD having a substitution degree of 6.6. However, isolated yields of the SBE-β-CD synthesized in this series of reports are between 60% and 70%.
In Chinese patent CN1858071A, after hydroxyl deprotonation by sodium metal in a 1,4-dioxane, a β-cyclodextrin is subjected to substitution reaction with a 1,4-sulfobutyrolactone. Filtering and washed with methanol is performed after the reaction to obtain a crude product. Desalting and purification of an aqueous solution of the crude product are performed using a glucose gel column (G-25), and the solution is concentrated and freeze dried to obtain a SBE-β-CD product. The method has a shortcoming that dangerous metal sodium is used as a reagent, the expensive glucose gel column is used in the purification, and the obtained SBE-β-CD product has a moderate yield of 49% to 51%.
Therefore, it is urgent to find a practical and feasible synthesis route which is simple in process, low in cost, high in yield, easy to operate and applicable to mass production so as to solve the problem existing in the prior art.